Obesity is increasing rapidly in the population and is a leading preventable cause of morbidity and mortality worldwide. Obesity reduces life expectancy and increases health problems including cardiovascular disease, diabetes and cancer. In particular, breast cancer in women is closely associated with obesity. Obese people get more cancer, worse cancer, and die more often from cancer than lean people. In spite of an epidemiological link between obesity and low cancer survival rates, little is known about the molecular mechanisms by which obesity affects the progression of breast cancer. Recently we identified a proinflammatory chemokine profile linking obesity and breast cancer. Because obesity is recognized as a chronic state of inflammation, crosstalk between adipocytes and breast cancer cells can drive the inflammatory burden via the elaboration of proinflammatory chemokines that promote cancer progression. This eventually is in part responsible for high mortality rates. This proposal will define the roles of obesity-promoted proinflammatory chemokines on the progression of breast cancer. We will clarify the role of this obesity-derived inflammatory burden via proinflammatory chemokines on the progression of breast cancer using CXCR2 knockout or obese mice. Because triple-negative breast cancer (TNBC) cells produce an enhanced level of proinflammatory chemokines in response to an inflammatory condition compared to non-TNBC cells, we will determine the molecular mechanisms by which obesity is involved in producing this higher proinflammatory chemokine burden in TNBC cells. As a preventive and therapeutic approach, we will evaluate the anti- adipogenic and anti-tumorigenic effects of afatinib (against epidermal growth factor receptor activation) and/or tempol (against obesity-related oxidative stress) on the progression of breast cancer via disruption of obesity- promoted proinflammatory chemokines. The findings will provide a deeper understanding of the role of proinflammatory chemokines that link obesity and the progression of breast cancer. It is envisaged that the results will suggest therapeutic strategies to improve women cancer survival, particularly for obese cancer patients, through drugs with anti-adipogenic and anti-tumorigenic effects. Finally, preventing and reducing obesity will provide a firm foundation for long-term survival of breast cancer patients and improve their quality of life.